1. Field of the Invention
The present invention generally relates to coronary heart attacks and cardiac surgery. More particularly, the invention is related to the use of histidine as a protective agent during cardiac surgery and during the ischemia/reperfusion phases of acute myocardial infarction (coronary heart attack).
2. Description of the Prior Art
Heart disease is the biggest cause of death in the Western world. There are many different forms of heart disease and disease states can develop from a number of different factors including stress, diet, tobacco use, and genetic make up of the individual. Ischemia is a heart disease condition characterized as a local anemia caused by mechanical obstruction or occlusion of the blood supply. Oxygen radicals have been implicated as important mediators of tissue injury during myocardial ischemia and reperfusion. A number of studies have shown that free radicals, particularly superoxide anions (.O.sub.2) and hydroxyl radicals are generated following reperfusion of the ischemic myocardium and have linked the free radical generation to the loss of contractile function. Superoxide anion is relatively unreactive and is considered dangerous because its dismutation results in the formation of hydrogen peroxide which can potentially generate the highly reactive hydroxyl radical (.OH) in the presence of transition metal ions. It is therefore generally believed that ultimate tissue damage occurs due to .OH radicals. Indirect proof for the involvement of .OH radicals in ischemia/reperfusion injury is derived from observations of a protective effect of .OH radical scavengers such as dimethylthiourea (DMTU), dimethylsulfoxide, and mannitol. In addition, certain agents which prevent the formation of hydroxyl radicals have also demonstrated a protective effect including deferoxamine, superoxide dismutase (SOD), and catalase.
Another active oxygen species is singlet molecular oxygen (.sup.1 O.sub.2). Singlet oxygen is not a radical; rather, it is an electronically excited state of oxygen which results from the promotion of an electron to higher energy orbitals. In Kukreja et al., Biochim. Biophys. A, 990:198-205 (1990), and Kukreja et al., Am. J. Physiol., 259:H1330-H1336 (1989), data was presented which demonstrated that superoxide anion or hydrogen peroxide are the least reactive species in damaging sarcolemma or sarcoplasmic reticulum. Therefore, it might be inferred that the only species believed to be injurious in myocardial tissue is .OH radical. However, .OH radical can initiate lipid peroxidation which can produce lipid free radicals that may become important sources of singlet oxygen in vivo. Hence, the damage often attributed to the .OH radical could be the resultant effects of other reaction intermediate products, including lipid free radicals and singlet oxygen.
Janero et al., J. Mol. Cell Cardiol., 21:1111-1124 (1989), showed that .alpha.-tocopherol provides cellular protection by acting as a chain breaker in the lipid peroxidation process, not by scavenging the .O.sub.2.sup.- radical per se. Singlet oxygen is also acted upon by .alpha.-tocopherol. Hearse et al., Circ. Res., 65:146-153 (1989), and Vandeplassche et al., J. Mol. Cell Cardiol., 22:287-301 (1990) (abstract) showed that .sup.1 O.sub.2 generated from exogenous sources is able to mimic ischemia/reperfusion induced myocardial damage. Tarr et al., J. Mol. Cell Cardiol., 21:539-543 (1989), recently reported that rose bengal, when applied extracellularly to frog atrial myocytes, induced a prolongation followed by a reduction of action potential duration. In addition, Donck et al., J. Mol. Cell Cardiol., 20:811-823 (1988) reported that isolated myocytes exposed to rose bengal light rapidly round up and experience ultrastructural injury.
In Kukreja et al., Abs. of 63rd Sci. Sess. (AHA) (Dallas), 1068 (1990), it was reported that singlet oxygen generated from photosensitization of rose bengal induced significant inhibition of calcium uptake and Ca.sup.2+ -ATPase activity in isolated sarcoplasmic reticulum. This damage caused by singlet oxygen could be significantly reduced using histidine, but not SOD or catalase. Misra et al., J. Biol. Chem., 265-15371-15374 (1990), reported that histidine is a scavenger of singlet oxygen. In contrast, SOD and catalase are scavengers of superoxide anion. Kim et al., Am. J. Physiol., 252:H252-H257 (1987), demonstrated histidine provides significant protection of sarcolemmal Na.sup.+ K.sup.+ -ATPase activity following ischemia/reperfusion in guinea pig hearts.
Electrocardiography is a well known technique for examining the condition of the heart. There are four chambers in the human heart. In operation, the right atrium receives venous blood from the body and pumps it into the right ventricle which pumps the blood through the pulmonary network where the blood becomes oxygenated by the lungs. The oxygenated blood is returned to the left atrium and is pumped into the left ventricle. The left ventricle is the most powerful chamber of the heart and serves the function of propelling the blood throughout the body network. Typically, 2,000 gallons of blood a day are pumped through the heart of a normal individual, and the heart keeps this pace throughout the life of the individual (e.g., seventy years or more). An electrocardiograph apparatus enables doctors to monitor electrical changes in the heart muscle. All the functions of the body are motivated by a complex electromechanical system which is controlled through the brain and central nervous system. Each cell within the body is surrounded by a membrane which is electrically "polarized", meaning they each have positive and negative ions on opposite sides of the membrane. Contraction of a heart muscle cell causes an electrical current flow due to the positive and negative ions. Because all of the heart cells are intimately connected, the heart organ acts as one very large cell. In the resting state (diastole), no current flows; however, as the heart expands and contracts, electrical current flows and can be sensed by electrodes.
Electrocardiography is the process of sensing and analyzing the current flow in the heart of a patient. Because the principal current detectable when a patient is at rest is produced by the heart, electrodes need not be connected directly to the heart. Typically, six or more electrodes are positioned on different portions of a patient's chest to sense the electric signals from the heart. The sensed signals are recorded on a monitor or strip chart and are referred to as an electrocardiogram. The electrocardiogram is often referred to as an ECG or EKG. According to a technique developed by Willem Einthoven in 1901, points on an ECG are labelled according to a PQRSTU system. FIG. 1 shows two cycles of a normal ECG trace where the waves are labelled PQRST. The P wave represents activity in the atria and the QRST waves represent ventricular activity. The heart's action is triggered by its own built-in pacing mechanism which comprises a bundle of specialized cardiac muscle fibers known as the sino-atrial node. The P wave represents the time taken for the electrical signal to travel throughout the muscle of the atria, whereas the QRS section represents the ventricular muscle being depolarized and the T section represents the ventricular repolarization. The U section (not shown) is often not detected and its meaning is not precisely known.
The ECG trace can provide several important pieces of information about the heart. One of the most important measurements to be made from the ECG trace is the PR interval. FIG. 2 highlights the PR interval on a single heart contraction pulse as well as other well understood portions of a single ECG trace. The PR interval is a measure of the time taken for the electrical impulse to travel through the atria to another specialized muscle bundle which synchronizes the actions of the atria and ventricles. Specifically, the PR interval is a recording of the cardiac impulse traveling to the atrio-ventricular (AV) node and the bundle of His, and then traversing the bundle branches and Purkinje fibers. The PR interval usually lasts 0.12 to 0.21 seconds. A longer period indicates a breakdown in the smooth operation of the AV node. The QRS section should last 0.06 to 0.11 seconds and longer periods typically indicate that the ventricles are acting sluggishly and not getting their electrical impulses simultaneously. The isoelectric ST segment and upright T wave follow the QRS section and represent ventricular repolarization. The ST segment is a sensitive indicator of myocardial ischemia or injury and should be on the isoelectric line.
Arrhythmia is a condition where the heart beats with, an irregularity in the force or rhythm. FIGS. 3 through 5 contrast the ECG of a normal sinus rhythm with ECG found for ventricular tachycardia and ventricular fibrillation, respectively. In the normal ECG of FIG. 3, there is a regularity in the P-P and R-R cycles, where the cycles are measured as the time between P and R segments of adjacent heart pulses. In ventricular tachycardia, as shown in the ECG of FIG. 4, there is a rapid and repetitive firing of ventricular premature contractions in a row. When the ventricles contract rapidly with this arrhythmia, the volume of blood ejected into the circulation is often inadequate. This kind of arrhythmia, if left untreated, often degenerates into fatal ventricular flutter or fibrillation. In ventricular fibrillation, as shown in the ECG of FIG. 5, there is no recognizable QRS complex and an extremely irregular rhythm. In this type of arrhythmia, virtually no blood is ejected into the systemic circulation, and death will occur if no corrective action is taken.
A major concern during cardiopulmonary bypass procedures is minimizing ischemic damage to the myocardium, thereby avoiding depressed myocardial performance in the post operative period. Prolonged ischemia such as that following myocardial infarction or occurring during long-term coronary bypass procedures causes serious damage to the myocardium. It has been suggested that free radicals are involved in the patho-physiology of ischemia-induced tissue damage. During ischemia, increased reducing equivalents are produced and this may favor the production of .O.sub.2 anion and other free radical species upon reoxygenation. Many and varied compounds have been reported to reduce the susceptibility of the heart to ischemia/reperfusion injury. These include agents which inhibit free radical production or facilitate their elimination. Other therapeutic agents include calcium channel blockers, prostacyclin analogs and thromboxane inhibitors, sodium channel blockers, and .alpha.- and .beta.-adrenergic receptor blockers. Some of these agents are effective against ischemia and reperfusion induced arrhythmias, whereas others are effective against only one or the other. Prior to this invention, there were no agents available, which abolish arrhythmias, improve contractility and protect ultrastructurally.